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Statins And Cirrhosis: Reducing Events of Decompensation (SACRED)

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ClinicalTrials.gov Identifier: NCT03654053
Recruitment Status : Not yet recruiting
First Posted : August 31, 2018
Last Update Posted : September 3, 2018
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
Tamar Taddei, VA Connecticut Healthcare System

Brief Summary:
This phase III, randomized, double-blind, placebo-controlled, multi-center study seeks to test whether simvastatin, a statin usually used to lower cholesterol to prevent heart problems and strokes, can lower the risk of hepatic decompensation (developing symptoms of cirrhosis) in U.S. Veterans who have compensated cirrhosis (the liver is scarred and damaged but there are no symptoms). The study will also explore how changes or differences in genes effect the safety and effectiveness of using statins and how the use of statins affects quality of life.

Condition or disease Intervention/treatment Phase
Cirrhosis Drug: Placebo Oral Tablet Drug: Simvastatin 40mg Phase 3

Detailed Description:

HMG-coA reductase inhibitors (statins), independent of cholesterol-lowering effects, are beneficial in liver diseases by reducing endothelial dysfunction, intrahepatic vasoconstriction, inflammation and fibrosis, and can reduce portal vein blood pressure. Clinically significant portal hypertension (hepatic vein wedge pressure greater than or equal to 10mmHg) is the most important predictor of decompensation and death in patients with cirrhosis.

This randomized, double-blind, placebo-controlled, multi-center Phase III interventional study seeks to demonstrate that statin therapy in patients with cirrhosis at high-risk for hepatic decompensation will reduce the incidence of hepatic decompensation, hepatocellular carcinoma or all-cause mortality.

Patients with compensated cirrhosis at high-risk for hepatic decompensation will be stratified based on the presence or absence of varices and randomized to simvastatin 40mg/day for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Additionally, the interaction of SLCO1B1 and KIF6 polymorphisms on safety and clinical efficacy of statin therapy and the impact of statin exposure on health-related quality of life in patients with compensated cirrhosis will be examined.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis
Drug Information available for: Simvastatin

Arm Intervention/treatment
Experimental: Simvastatin
Simvastatin 40mg PO once at bedtime for up to 24 months. Note: all enrolled subjects will trial 20mg once at bedtime for two weeks as lead-in to determine tolerability prior to randomization.
Drug: Simvastatin 40mg
Simvastatin 40mg taken once nightly at bed time.
Other Name: Simvastatin

Placebo Comparator: Placebo
Placebo 40mg PO once at bedtime for up to 24 months.
Drug: Placebo Oral Tablet
Placebo taken once nightly at bed time.
Other Name: Placebo




Primary Outcome Measures :
  1. Survival free from hepatic decompensation [ Time Frame: 24 months ]
    Occurrence of hepatic decompensation measured by first variceal hemorrhage, or development of ascites, or onset of hepatic encephalopathy, or hepatocellular carcinoma.


Secondary Outcome Measures :
  1. Liver-related death [ Time Frame: 24 months ]
    Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation

  2. Survival free from major cardiac events [ Time Frame: 24 months ]
    Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.

  3. Change in patient health-related quality of life [ Time Frame: 12 months ]
    Clinically significant change in score from baseline to month 12 as assessed by the Chronic Liver Disease Questionnaire (CLDQ)

  4. Statin-related hepatotoxicity [ Time Frame: 24 months ]
    Occurrence of hepatotoxicity defined as Grade ≥ 3 liver toxicity per CTCAE 5.0 (≥ 5 times upper limit of normal as defined by local laboratory- transaminases)

  5. Myositis [ Time Frame: 24 months ]
    Occurrence of myositis defined as either Grade ≥ 3 myositis (pain associated with severe weakness; limiting self care Activities Daily Living {ADL}) OR Grade ≥ 4 creatine phosphokinase by CTCAE 5.0 (≥ 10x upper limit of normal)

  6. Rhabdomyolysis [ Time Frame: 24 months ]
    Occurrence of rhabdomyolysis defined as Grade ≥ 3 (symptomatic, urgent intervention indicated)

  7. Hepatotoxicity [ Time Frame: 24 months ]
    Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • U.S. Veteran
  • Cirrhosis due to chronic viral hepatitis, or alcohol or non-alcoholic fatty liver
  • Compensated cirrhosis (history of endoscopically-confirmed variceal hemorrhage, absence of overt ascites, history of overt non-precipitated encephalopathy)
  • Age ≥ 18 and ≤ 80
  • High risk of cirrhosis decompensation as defined by any of the following:

    • Presence of esophageal varices on endoscopy
    • Presence of portosystemic collaterals on imaging as determined by a body radiologist
    • Fibroscan VCTE ≥ 25kPa
    • Platelet count ≥ 70 K/mm
    • ≥ 60 total points (~67% of clinically significant portal hypertension using the ANTICIPATE Nomogram)
  • Competent to provide informed consent

Exclusion Criteria:

  • Prior exposure to any statin within 2 years
  • Prior allergy or sensitivity to simvastatin
  • History of variceal hemorrhage confirmed endoscopically within the previous 2 years
  • Presence of overt ascites or treatment with diuretics for ascites
  • History of chronic, recurrent or episodic overt hepatic encephalopathy with asterixis
  • History of hepatocellular carcinoma
  • Child-Turcotte-Pugh C Stage (CTP Score ˃ 9)
  • Prior receipt of organ transplant
  • Participation in another pharmacological clinical trial within 3 months of the current study
  • Pregnancy or anticipated pregnancy within 2 years
  • Breast Feeding
  • Patients with life expectancy ˂ 3 years due to comorbid conditions
  • Independent indication for initiation of statin therapy
  • Patients with any form of clinical atherosclerotic cardiovascular disease (ASCVD)
  • Patients with primary LDL-C ≥ 190 mg/dl
  • Patients with diabetes mellitus, age 40-75 years, with LDL-C levels of 70-189 mg/dl
  • Patients without diabetes, age 40-75 years, with an estimated 10-year ASCVD risk ≥ 7.5%
  • Need for concomitant administration of potent inhibitors of CYP34A4 enzymes (medications or other supplements that should not be taken with simvastatin, including cyclosporine, danazol, gemfibrozil, fenofibrate, extended release niacin, itraconazole, ketoconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, macrolide antibiotics - erythromycin, clarithromycin, telithromycin, nefazadone, verapamil, diltiazem, dronedarone, amiodarone, renolazine, lomitapide, and cobicistat)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654053


Contacts
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Contact: Rajni Mehta 203.932.5711 ext 2228 rajni.mehta@va.gov
Contact: David Kaplan, MD 215.823.5800 ext 6729 dakaplan@pennmed.edu

Sponsors and Collaborators
Tamar Taddei
United States Department of Defense
Investigators
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Principal Investigator: Tamar Taddei, MD VACHS, Yale University School of Medicine

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Responsible Party: Tamar Taddei, Associate Professor, VA Connecticut Healthcare System
ClinicalTrials.gov Identifier: NCT03654053     History of Changes
Other Study ID Numbers: VOCAL-001
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: September 3, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Tamar Taddei, VA Connecticut Healthcare System:
cirrhosis
hepatic decompensation

Additional relevant MeSH terms:
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Fibrosis
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors